One limitation of current vaccine strategies is the inability to generate effective memory CD8 T cell responses in the correct location. There is a gap in our knowledge of how these memory CD8 T cells are generated and maintained in vivo in different tissues. In response to vaccination, CD8 T cells expand, differentiate into effectors and then undergo contraction. The end result is a population of memory CD8 T cells that survive this process. The proposed research intends to determine if rapamycin, an immunosuppressive drug, in combination with IL-15 can generate and maintain enough memory CD8 T cells in non-lymphoid tissues that are capable of eliminating tumors and or pathogens. While it is well accepted that rapamycin treatment can prevent rejection of organ transplants, by suppressing the immune system, it can also increase the number of viral memory CD8 T cells found within secondary lymphoid tissues. The factors that account for the discrepancy observed with rapamycin treatment on pathogen-specific versus graft-specific T cells are unclear. We propose that one possibility is that rapamycin induced CD8 T cells are confined to secondary lymphoid tissues and without addition cues cannot migrate to non-lymphoid tissues. Thus in Specific Aim 1 we will determine the impact of mTOR inhibition and IL-15 signaling on tissue distribution of CD8 and CD4 T cells in vivo. We will investigate whether IL-15 can enhance the migration of rapamycin induced memory CD8 T cells into non-lymphoid tissues and the specific mechanisms by which this occurs. In Specific Aim 2 we will characterize the functional consequences of combining mTOR inhibition with IL-15 on tumor growth and anti-tumor immunity. These studies will provide insight into whether inhibition of mTOR and IL-15 therapy will result in an increase i memory CD8 T cells in non-lymphoid tissues that have the ability to be sustained. It will also determine if this therapy has any anti-tumor effects. The proposed research is significant, because it has implications for both current immunotherapies and for the better design of vaccines.